The degeneration of 50–70% of the population of dopaminergic neurons in the human brain results in the profound disturbances of motor function that are characteristic of Parkinson's Disease (PD). As this degeneration of neurons progresses, the symptoms become increasingly severe, leading not only to loss of motor function but also to an increased incidence of dementia and other neurological disorders. Currently, over a million people in North America are affected by this disease whose single most consistent risk factor is age. Because the population of the elderly is expected to increase over the next four decades, it is projected that neurodegenerative diseases, such as Parkinson's Disease, may pass cancer as the second most common cause of death among the elderly. Therefore, the development of therapeutic agents that can delay the onset of disease, slow its progression, or enhance the effectiveness of other drugs, will provide a substantial contribution to reducing the mortality and morbidity due to Parkinson's Disease among the elderly and increasing the quality of life for afflicted individuals.
Treatment of Parkinson's Disease has traditionally been subdivided into three categories: preventive, symptomatic and restorative intervention. The latter intervention, which include transplantation of adrenal medulla cells, intraventricular delivery of dopaminergic neurotrophic factor GDNF, and gene therapy, are in very early stages of safety and efficacy trials. Protective therapy with selective monoamine oxidase B (MAO-B) inhibitors, such as selegiline, has been unproductive to date. Early trials, which indicated promise, could largely be explained through amelioration of symptoms rather than by slowing the progression of the disease. As a result, most of the current efforts continue to focus on therapeutic agents that affect symptoms which accompany the disease rather than to reverse or prevent it. This remains an important area for medical research, due to the problems that exist with current therapeutic interventions.
Evaluation of the literature indicates that levodopa (L-DOPA) still remains the agent of choice for the initial treatment of PD. There is clearly a beneficial motor response to this drug during the early states of the disease, however, as the disease progresses, the effectiveness of the drug is reduced and other side effects become more pronounced. Patients may experiece fluctuations in motor response, dyskineasias, or psychiatric disturbances, such as nightmares, hallucinations, psychosis or depression. Alternatives, for example, the use of amantidine, selegiline or anti-cholinergic agents may provide some initial benefit, but in most cases patients still require levodopa or other dopamine (DA) agonists for effective symptomatic relief. Even the DA agonists, when used as monotherapeutic agents, often fail to exceed the effectiveness of levodopa.
The declining efficacy of the major therapeutic agents and the appearance of other manifestations during the course of the disease suggest additional therapeutic strategies. Among the proposed directions are new formulations of levodopa to improve the delivery of the drug to the affected region of the brain, selective serotonin reuptake inhibitors (SSRI's) and monoamine oxidase inhibitors (MAO I) to treat depression in PD patients, dopamine transporter (DAT), and catechol O-methyl transferase (COMT) inhibitors to prolong the effects of DA, and DA receptor (D1) agonists to reduce dyskinesias. All of these approaches utilize separate discrete molecular entities to elicit the desired response, either alone or in combination with other agents. As such, they are subject to limitations often associated with combination therapy, for example, noncompliance due to different dosing schedules and drug-drug interactions.
As shown in FIG. 1, which depicts a model dopaminergic neuron, in addition to having the processes for dopamine synthesis, this region contains the dopamine transporter (DAT) which is responsible for removal of dopamine from the synapse, catechol O-methyl transferase (COMT) and monoamine oxidases (MAO-A and B) which are involved in DA metabolism, and DA receptors (D1, D2, D2, etc.) which mediate dopaminergic responses. Thus, intervention at one site alone or selectively, as is the common for traditional therapeutics, may only produce a partial response because of compensatory mechanisms mediated by the other sites. Because of this decreased response, often a greater dose must be utilized which often results in adverse side effects. In contrast, an intervention strategy which affects several sites at a dose level that may be ineffective if present solely, may produce an additive response that would be therapeutically beneficial, while reducing the possibility for adverse side effects. Although FIG. 1 depicts the dopaminergic neuron, it will be appreciated that other regions having multiple receptor sites in close proximity may be involved in other diseases and conditions, and thus also may utilize this intervention strategy.
Clearly, because of the need to increase the efficacy and safety of pharmaceuticals, it would be beneficial to develop pharmaceuticals which contain multiple pharmacophoric sites capable of interacting at multiple biological sites, preferably for those biological sites which act in concert, implicated in specific diseases and conditions and/or involved in side effects of these diseases or conditions.